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2Department of Bioethics, Case Western Reserve University School of Medicine, Cleveland, OH, USA

A timely and thoughtful discussion of the ethical challenges and societal impacts presented by the recent reports demonstrating the successful in vitro generation of functional gametes from somatic and pluripotent stem cells.

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Angiomyolipoma (AML) research is hampered by the lack of an animal model. In a novel in vivo human AML model, PPARG inhibition is identified as a potential therapy and the AML cell of origin as a resident MSC/pericyte skewed toward adipogenic differentiation.

Synopsis

Angiomyolipoma (AML) research is hampered by the lack of an animal model. In a novel in vivo human AML model, PPARG inhibition is identified as a potential therapy and the AML cell of origin as a resident MSC/pericyte skewed toward adipogenic differentiation.

An AML xenograft (Xn) model, exhibiting the classic histology, immunophenotype, and gene expression pattern of human AML, was established by injection of human AML cells in mice.

PPARG is expressed across all tumor compartments, indicating that rather than accompanying adipocytic differentiation, PPARG activation drives AML growth, and with the presence of fat in the tumor being its by‐product.

PPARG antagonism, via small molecules and shRNA, results in strong growth inhibition of AML, as well as abrogation of tumor initiation in mice.

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A Y RNA fragment enriched in extracellular vesicles from cardiosphere‐derived cells was identified and found to increase IL‐10 expression and secretion in macrophages. The fragment confers cardioprotection after ischemic injury in a rat model.

Synopsis

A Y RNA fragment enriched in extracellular vesicles from cardiosphere‐derived cells was identified and found to increase IL‐10 expression and secretion in macrophages. The fragment confers cardioprotection after ischemic injury in a rat model.

A Y RNA fragment is the most abundant small RNA species in extracellular vesicles secreted from cardiosphere‐derived cells.

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Why heart regeneration in mice is no longer possible after the age of 7 days remains unknown. Here, the robust downregulation of cardiac GATA4 levels occurring around the same time is shown to be at least in part responsible for this phenomenon.

Synopsis

Why heart regeneration in mice is no longer possible after the age of 7 days remains unknown. Here, the robust downregulation of cardiac GATA4 levels occurring around the same time is shown to be at least in part responsible for this phenomenon.

Cardiac GATA4 expression is strongly downregulated (by about 70–80%) between postnatal day 1 (P1) and P7 in parallel with the loss of regenerative capacity of the heart.

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Mutations in PANK2 cause PKAN disease. This belongs to a group of disorders characterized by progressive neurodegeneration and excessive iron deposition in the brain. PANK2 enzyme catalyzes the first step in CoA synthesis. iPSC‐derived neurons from PKAN patients display abnormal phenotypes.

Synopsis

Mutations in PANK2 cause PKAN disease. This belongs to a group of disorders characterized by progressive neurodegeneration and excessive iron deposition in the brain. PANK2 enzyme catalyzes the first step in CoA synthesis. iPSC‐derived neurons from PKAN patients display abnormal phenotypes.

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Congenital and drug‐induced long‐QT syndrome (LQTS) can be rescued in vitro by a new hERG allosteric activator. Isogenic pairs of human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) prove to be a reliable tool for drug screening and safety pharmacology.

Synopsis

Congenital and drug‐induced long‐QT syndrome (LQTS) can be rescued in vitro by a new hERG allosteric activator. Isogenic pairs of human pluripotent stem cell‐derived cardiomyocytes (hPSC‐CMs) prove to be a reliable tool for drug screening and safety pharmacology.

The small molecule LUF7346 is a potent and selective type‐1 hERG activator.

Congenital LQTS, drug‐induced LQTS and a combination of the two were rescued by hERG activation.

Electrophysiological phenotype differences exist among CMs derived from different control lines.

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This is the first proof‐of‐principle that induced pluripotent stem cell (iPSC)‐derived dopaminergic neurons (DAn) from sporadic and monogenetic Parkinson's disease (PD) patients show the same epigenomic changes as compared to healthy controls.

Synopsis

This is the first proof‐of‐principle that induced pluripotent stem cell (iPSC)‐derived dopaminergic neurons (DAn) from sporadic and monogenetic Parkinson's disease (PD) patients show the same epigenomic changes as compared to healthy controls. For a video version of this synopsis, see: http://embopress.org/video_EMM-2015-05439.

Epigenomic changes are common in patients with sporadic PD and patients with a monogenic form of PD associated with mutations in the gene LRRK2.

PD‐associated methylation changes are latent in parental somatic cells or undifferentiated iPSCs and become uncovered upon differentiation into DAn (cells targeted in PD) but not into other neural types.

PD‐associated methylation changes correlate with gene expression, target functionally‐ active sequences (enhancers), and are related to the aberrant down‐regulation of a network of transcription factors relevant to PD.

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Allogeneic hematopoietic stem cell transplantation still has a high risk of post‐transplant complications including graft versus host disease and relapse of malignancy. Detection of single nucleotide polymorphisms may help to provide a risk‐adapted treatment.

Synopsis

Allogeneic hematopoietic stem cell transplantation still has a high risk of post‐transplant complications including graft versus host disease and relapse of malignancy. Detection of single nucleotide polymorphisms may help to provide a risk‐adapted treatment.

The MICA‐129Met/Val dimorphism was associated with an increased survival and a reduced risk to die due to acute graft versus host disease in a cohort of 452 patients.

The survival of MICA‐129Val/Val genotype carriers was improved when treated with antithymocyte globulin (ATG).

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Comprehensive overview on how reprogramming and transdifferentiation can be exploited to generate induced pluripotent stem cell‐derived cardiomyocytes and induced cardiomyocytes to advance discovery and accelerate translation to the clinic.

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